title: Elevated levels of circulating DNA and chromatin are independently associated with severe coronary atherosclerosis and a prothrombotic state.
abstract: OBJECTIVE
  Aberrant neutrophil activation occurs during the advanced stages of atherosclerosis. Once primed, neutrophils can undergo apoptosis or release neutrophil extracellular traps. This extracellular DNA exerts potent proinflammatory, prothrombotic, and cytotoxic properties. The goal of this study was to examine the relationships among extracellular DNA formation, coronary atherosclerosis, and the presence of a prothrombotic state.
  
  
  RESULTS
  In a prospective, observational, cross-sectional cohort of 282 individuals with suspected coronary artery disease, we examined the severity, extent, and phenotype of coronary atherosclerosis using coronary computed tomographic angiography. Double-stranded DNA, nucleosomes, citrullinated histone H4, and myeloperoxidase-DNA complexes, considered in vivo markers of cell death and NETosis, respectively, were established. We further measured various plasma markers of coagulation activation and inflammation. Plasma double-stranded DNA, nucleosomes, and myeloperoxidase-DNA complexes were positively associated with thrombin generation and significantly elevated in patients with severe coronary atherosclerosis or extremely calcified coronary arteries. Multinomial regression analysis, adjusted for confounding factors, identified high plasma nucleosome levels as an independent risk factor of severe coronary stenosis (odds ratio, 2.14; 95% confidence interval, 1.26-3.63; P=0.005). Markers of neutrophil extracellular traps, such as myeloperoxidase-DNA complexes, predicted the number of atherosclerotic coronary vessels and the occurrence of major adverse cardiac events.
  
  
  CONCLUSIONS
  Our report provides evidence demonstrating that markers of cell death and neutrophil extracellular trap formation are independently associated with coronary artery disease, prothrombotic state, and occurrence of adverse cardiac events. These biomarkers could potentially aid in the prediction of cardiovascular risk in patients with chest discomfort.
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.|Department of Pediatrics, Harvard Medical School, Boston, MA, USA.|Laboratory for Clinical Thrombosis and Hemostasis, Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Julian I
authors.initials: JI
authors.lastname: Borissoff
authors.affiliation: Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Ivo A
authors.initials: IA
authors.lastname: Joosen
authors.affiliation: Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Mathijs O
authors.initials: MO
authors.lastname: Versteylen
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.|Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Brill
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.|Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
authors.forename: Tobias A
authors.initials: TA
authors.lastname: Fuchs
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.|Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Savchenko
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Maureen
authors.initials: M
authors.lastname: Gallant
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.|Immunology Graduate Program, Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Martinod
authors.affiliation: Laboratory for Clinical Thrombosis and Hemostasis, Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Hugo
authors.initials: H
authors.lastname: Ten Cate
authors.affiliation: Cardiology Center Netherlands, Utrecht, The Netherlands.
authors.forename: Leonard
authors.initials: L
authors.lastname: Hofstra
authors.affiliation: Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Harry J
authors.initials: HJ
authors.lastname: Crijns
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.|Department of Pediatrics, Harvard Medical School, Boston, MA, USA.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Denisa D
authors.initials: DD
authors.lastname: Wagner
authors.affiliation: Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.|Department of Radiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Bas L J H
authors.initials: BLJH
authors.lastname: Kietselaer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D002843:Chromatin / Q000378:metabolism*; D003324:Coronary Artery Disease / Q000000981:diagnostic imaging* / Q000453:epidemiology / Q000378:metabolism*; D003430:Cross-Sectional Studies; D004247:DNA / Q000097:blood*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism; D009707:Nucleosomes / Q000378:metabolism; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012307:Risk Factors; D012720:Severity of Illness Index; D013927:Thrombosis / Q000175:diagnosis* / Q000453:epidemiology / Q000378:metabolism*; D014057:Tomography, X-Ray Computed; D014841:von Willebrand Factor / Q000276:immunology / Q000378:metabolism
chemical_list: D015415:Biomarkers; D002843:Chromatin; D009707:Nucleosomes; C029417:Von Willebrand antigen; D014841:von Willebrand Factor; D004247:DNA
keywords: DNA; atherosclerosis; chromatin; coagulation, blood; neutrophils; nucleosomes; thrombin; thrombophilia